IgA protease is an extracellular enzyme produced by Streptococcus sanguis and found in human cariogenic dental plaque. This uniquely specific enzyme cleaves and inactivates human IgA1. The teeth and oral mucosal tissues are dependent for immune defense on secretory IgA found in saliva. IgA protease may thus function as a virulence factor by fostering S. sanguis and, possibly, S. mutans colonization of these entities. Our hypothesis is that reduction of tooth colonization and subsequent diminution in dental caries may be achieved by specific inhibition of both IgA protease and other bacterial enzymes. The long-term goal of this research is to identify drugs that will accomplish this objective. We propose to purify the IgA protease from S. sanguis to homogeneity in order to study its molecular characteristics, substrate specificity, and sensitivity to endogenous inhibitors. In addition, simple rapid assays based on synthetic peptides modeled on the hinge region of IgA1 will be developed. These peptides should contain various unique functional groups which may be identified after cleavage of the substrate by the enzyme. Since the conformations of both the IgA1 hinge region and the synthetic substrates appear to be important factors in the rate of cleavage, these will be studied by advanced magnetic resonance techniques. Lastly, we propose to develop inhibitors of the IgA1 hydrolase which may be used either systemically or applied topically to the tooth. In summary, S. sanguis elaborates a proteas which inactivates IgA and may foster caries formation by permitting colonization of the tooth by both this and other bacteria. We propose to purify the enzyme, prepare rapid simple assays for its localization, and develop drugs which prevent its activity. This objectives of this program are to clarify the role of the IgA protease in caries formation and, hopefully, result in a significant reduction in dental disease.